The invention relates generally to compounds active against viral diseases and, more specifically, to bicyclic carbohydrates that are active against infections caused by the alphaherpesvirinae HSV-1 and HSV-2.
Infections by herpes viruses are among the most common and easily transmitted viral conditions. Numerous distinct viruses have been identified and the treatment by chemotherapeutic agents of diseases caused by some of these, such as HSV-1, HSV-2 and VZV (varicella-zoster virus), has produced substantial clinical benefit.
The genomic linear double-stranded DNA of the herpes viruses codes for about 100 polypeptides. While the functions of most of the encoded proteins are poorly understood, a number of them are well characterized and include enzymes which provide excellent targets, or have vital implications, for chemotherapy. These include a DNA polymerase essential for replication, a protease and, significantly for HSV-1, HSV-2 and VZV, a thymidine kinase. Anti-herpes virus agents often show a broad spectrum of activity across the family, a consequence of structural similarities between the functional proteins, although the presence or absence of the thymidine kinase is usually a key factor in selectivity.
Herpes simplex viruses type 1 and 2 cause a broad spectrum of diseases in humans including labial and genital herpes (R. J. Whitley. Herpes simplex viruses. in Fields virology (eds. B. N. Fields, D. M. Knipe and P. M. Howley) 2297–2342 (Raven, New York, 1995)). The diseases all could be caused by either virus, though HSV-1 primarily affects the upper part of the body whereas HSV-2 is more commonly associated with genital infections. Although HSV diseases are not usually life threatening, recurrences can dramatically affect the quality of life of afflicted individuals. Nucleoside analogs such as acyclovir, valacyclovir, famciclovir and penciclovir have been approved as the drugs of choice for the treatment of HSV infections (C. M. Perry, D. Faulds. Valacyclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs 52, 754–772 (1996)).
These drugs inhibit the viral DNA polymerase after activation by the viral thymidine kinase (R. A. Vere Hodge. Famciclovir and penciclovir. The mode of action of famciclovir including its conversion to penciclovir. Antiviral Chem. Chemother. 4, 67–84 (1993); J. E. Reardon and T. Spector. Acyclovir: mechanism of action and potentiation by ribonucleotide reductase inhibitors. in Advances in Pharmacology (ed. T. Augusta) 1–27 (Academic, New York, 1991)).
Acyclovir, as a treatment for HSV infections, was the first example of a genuinely selective antiviral agent. Via some interactions acyclovir slows down the DNA-replication. However, it is only the triphosphate of acyclovir that interacts with the virus-specific DNA polymerase (P. A. Furman, M. H. StClair, J. A. Fyfe, J. L. Rideout, P. M. Keller, G. B. Ellion. J. Virol. 32, 72 (1979)). Acyclovir triphosphate (ACV-TP) itself is formed via its mono- and diphoshate intermediates. Already in the first step, the conversion of ACV in its monophosphate form, the first point of selectivity can be found. This step is carried out by an enzyme coded by the virus, viral coded thymidine kinase (TK), which can only be found in virally infected cells. Nevertheless there are cellular counterparts, cellular thymidine kinases, but they show much higher substrate specificity. The viral enzyme is less specific and will recognize a larger diversity of nucleosides as substrate. This is why only in the viral infected cell acyclovir is converted by TK to its monophosphate, which is converted into the triphosphate by cellular enzymes. This is the first aspect of the selectivity of acyclovir: the triphosphate is only formed in infected cells. The obtained ACV-TP then acts as an inhibitor of DNA-polymerase. This is the second step in the selectivity process, since ACV-TP inhibits viral coded DNA polymerase stronger than that in healthy cells. As soon as ACV-TP is incorporated in the growing DNA-chain, it will act through the absence of a 3-OH group as a chain terminator (the same principle as AZT). Additionally the viral DNA polymerase is irreversibly bound to the ACV nucleotide it attached to the DNA chain. In this way the growth of the viral DNA chain as well as the availability of the viral DNA polymerase is diminished, which hampers viral replication severely.
Clinical isolates and, especially, laboratory mutant strains can be resistant to acyclovir and other nucleosides. Many of these strains have deleted or altered the thymidine kinase, which makes them unable to phosphorylate nucleosides. TK function is not vital to the survival of HSV, though it may be able to increase replication rates. In vitro methods have produced acyclovir resistant phenotypes, which have an alteration in the function of the DNA polymerase. These are potentially a bigger problem, but so far appear to be of little clinical significance. When acyclovir resistance causes significant problems, foscarnet is used; however, mutants where acyclovir resistance is due to altered DNA polymerase function can also be resistant to foscarnet and phosphonate isosters of nucleoside monophosphates. Nucleoside-resistant HSV infections are increasingly encountered in immunocompromised individuals (D. W. Kimberlin et al. Antiviral resistance in clinical practice. Antiviral Res. 26, 423–438 (1995)). Therefore, pharmacologically distinct anti-HSV agents with significantly improved therapeutic efficacy are developed, such as HSV helicase-primase inhibitors (J. J. Crute et al. Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nature Med. 8, 386–391 (2002)) or inhibitors that block protein-protein interactions (N. Moss et al. Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase with improved in vivo antiviral activity. J. Med. Chem. 39, 4173–4180 (1996)).
Alternative compounds with activity against herpes viruses such as HSV-1 and HSV-2 are needed.